Xanthenyl semicarbazides

ABSTRACT

4-(9-Xanthenyl)semicarbazide and thiosemicarbazide, 4-(9-thiaxanthenyl)semicarbazide and thiosemicarbazide, and derivatives of these compounds, useful as anti-secretory agents.

This application is a division of application Ser. No. 277,410, filed2nd Aug. 1972, now U.S. Pat. No. 3,842,178, issued 15th Oct. 1974, whichapplication in turn is a division of our copending Application Ser. No.858,183, filed Sept. 15th, 1969, now U.S. Pat. No. 3,686,218, issued22nd Aug. 1972, which in turn is a continuation-in-part of ourapplication Ser. No. 662,587, filed 23rd Aug. 1967, now U.S. Pat. No.3,644,420, the entire disclosure of which is incorporated herein byreference. The subject matter of this application was subjected to arequirement for restriction in application Ser. No. 858,183, Paper No.4.

The invention relates to new derivatives of xanthen and thiaxanthenwhich have valuable biological activity.

According to one feature of the invention there are provided compoundsof formula I ##EQU1## wherein Xn represents the group ##SPC1##

In which X₁ and X₂ are oxygen or sulphur;

The rings A and B may optionally contain substituents selected fromhalogen, alkyl, alkoxy and hydroxy;

R₁ is hydrogen, alkyl, substituted alkyl, alkenyl, cycloalkyl, hydroxy,alkoxy, acyloxy or trialkylsilyloxy;

R₂ is hydrogen, alkyl, substituted alkyl, alkenyl, cycloalkyl, alkanoyl,or alkoxycarbonyl;

R₃ is hydrogen, alkyl, substituted alkyl, alkenyl, cycloalkyl, oralkoxy;

R₄ is hydrogen, alkyl, substituted alkyl, alkenyl, cycloalkyl, alkanoyl,or alkoxycarbonyl;

Or R₂ and R₃ taken together represent --(CH₂)_(m) --, where m is 3 or 4,and one of the --CH₂ -- groups may be replaced by >CO;

or R.sub. 3 and R₄ together with the nitrogen atom to which they areattached form a saturated 5-7 membered heterocyclic ring, optionallycontaining an additional hetero group selected from >NH, O, Sor >N-lower alkyl;

Together with pharmaceutically acceptable acid addition salts ofcompounds of formula I;

and, when R₃ and R₄ each represent alkyl, substituted alkyl, or alkenyl,or together form a ring as hereinbefore defined, pharmaceuticallyacceptable quaternary salts of compounds of formula I.

The term "substituted alkyl" includes alkyl radicals containingsubstituents such as hydroxy, halogen, amino, alkanoylamino,alkoxycarbonylamino, alkylamino, alkanoyl(alkyl)amino,alkoxycarbonyl(alkyl)amino, dialkylamino, aryl, aryloxy, alkoxy,acyloxy, and carboxy (in free acid, salt or ester form).

"Alkanoyl" and "alkoxycarbonyl" preferably indicate such groupscontaining up to 8 carbon atoms.

"Acyl" indicates the acyl residue of a carboxylic acid; such acidsinclude aliphatic carboxylic acids, preferably C₁ ₋₈, aromaticcarboxylic acids, heterocyclic carboxylic acids, carbonic acids,N-alkylcarbamic acids, N,N-dialkylcarbamic acids, N-phenylcarbamic acid,N,N-tetramethylene carbamic acid, N,N-pentamethylenecarbamic acid,N,N-3-oxapentamethylenecarbamic acid andN,N-3-thiapentamethylenecarbamic acid.

"Alkyl" whenever used above preferably indicates lower alkyl, containingup to 7 carbon atoms.

Acids which may be used in the quaternary salts defined above may be anyconventional quaternisation acids which lead to pharmaceuticallyacceptable salts, for example HX (where X is halogen) andtoluenesulphonic acids.

The methods that can be used to prepare the compounds of formula Idepend to some extent upon the nature of R₁ ₋₄ ; by way of example thefollowing typical methods are shown:

a. by reaction of a xanthydrol or thiaxanthydrol of formula XnOH (or anester thereof) with a compound of formula II ##EQU2## b. by reaction ofa compound of formula III

    XnNCX.sub.1                                                III

with a hydrazine of formula IV

    r.sub.2 nh -- nr.sub.3 r.sub.4                             iv

c. by reaction of a compound of formula V

    xnCON.sub.3 V

with a hydrazine of formula IV;

d. by reaction of a compound of formula VI ##EQU3## wherein X ishalogen, with a hydrazine of formula IV. Obvious chemical equivalents(in this type of reaction) of compounds of formula VI may also be usedsuch as compounds of formula VI wherein X is N₃, NCX₁ or --X₁ -acyl;

e. by reaction of a compound of formula VII

    xn -- Y                                                    VII

with a compound of formula VIII ##EQU4## in which one of Y and Z is ahalogen atom and the other is one equivalent of a metal, preferablysodium, potassium or lithium;

f. by reaction of an ester of a compound of formula IX ##EQU5## with ahydrazine of formula IV; preferred esters include those of formulae Xand XI ##EQU6## g. by reaction of a compound of formula XII

    xn -- NHR.sub.1                                            XII

with a carbazoylating or thiocarbazoylating agent capable of providingthe ##EQU7## group; examples of such agents, which are chemicalequivalents in this type of reaction, are the following:

1. an ester of a compound of formula XIII ##EQU8## a preferred ester isR₃ R₄ N--N(R₂)C(O)S-Phenyl; 2. a compound of formula XIV ##EQU9## p1wherein X is halogen or an obvious chemical equivalent (in this type ofreaction) such as N₃, NCX₁ or --X₁ -acyl; 3. a compound of formula XV##EQU10## and 4. a compound of formula XVI ##EQU11## h. by reduction ofa compound of formula XVII ##SPC2##

by conventional means, for example by hydrogenation in the presence ofstandard catalysts such as platinum, palladium, and the like, to give acompound of formula I wherein R₁ is hydrogen;

i. by reduction of a compound of formula XVIII ##EQU12## in which R₅ isalkylidene, cycloalkylidene or alpha-alkoxyalkylidene to give a compoundof formula I wherein one or both of R₃ and R₄ are hydrogen; reduction iscarried out by conventional means, for example by hydrogenation in thepresence of standard catalysts such as platinum, palladium, and the likeor by the use of sodium in a lower alkanol;

j. by reductive alkylation of a compound of formula XIX ##EQU13## byconventional means, for example using an an aldehyde or ketone offormula R₆ COR₇ (wherein R₆ is alkyl and R.sub. 7 is hydrogen or alkyl)and hydrogen in the presence of a standard catalyst such as platinum,palladium, and the like, to give compounds of formula I wherein R₃ ishydrogen and R₄ is alkyl.

k. by alkylation, alkanoylation or alkoxycarbonylation by conventionalmeans of a compound of formula I in which at least one of R₁ ₋₄ is ahydrogen atom to give the corresponding N-alkyl, N-alkanoyl orN-alkoxycarbonyl compound.

1. by N-alkanoylation, N-alkoxycarbonylation or O-acylation byconventional means of a compound of formula I containing an NH or OHgroup to give the corresponding N-alkanoyl, N-alkoxycarbonyl or O-acylcompound;

m. by dealkanoylation, dealkoxycarbonylation or deacylation of acompound of formula I containing an N-alkanoyl, N-alkoxycarbonyl orO-acyl group respectively to give the corresponding >NH or --OHcompound;

n. by alkylation or trialkylsilylation of a compound of formula Icontaining an OH group to give the corresponding alkoxy ortrialkylsilyloxy compound;

o. by hydrogenolysis of a compound of formula XX ##EQU14## wherein R_(o)is a protecting group readily removable by hydrogenolysis; a preferredprotecting group R_(o) is benzyl, but chemical equivalents (in this typeof reaction) of this group will be readily apparent to the skilledchemist; examples include methyl substituted by 2 or 3 phenyl groups,methyl substituted by 1, 2 or 3 p-nitrophenyl, p-methoxyphenyl or4-pyridyl groups, alkylsulphonyl, arylsulphonyl, arylthio, substitutedarylsulphonyl and substituted arylthio; hydrogenation is carried out byconventional means in the presence of standard catalysts such asplatinum, palladium, and the like;

p. by reaction of a compound of formula I wherein R₃ and R₄ eachrepresent alkyl, substituted alkyl, or alkenyl or together form a ringas hereinbefore defined with a conventional quaternising agent such asan alkyl halide, an alkyl p-toluene sulphonate, and the like, to form apharmaceutically acceptable quaternary salt;

q. by reduction by conventional means of a compound of formula XXI##EQU15## wherein n is 1 or 2 to give a compound of formula I wherein R₃and R₄ are hydrogen; as an example, reduction may be carried out byhydrogenation in the presence of standard catalysts such as platinum,palladium and the like;

r. by reaction of a 3-(9-xanthenyl)rhodanine or a correspondingthiaxanthenyl compound with a hydrazine compound of formula IV;

s. by reaction of a compound of formula XXII ##EQU16## with a hydrazineof formula IV; and t. by reaction of a compound of formula XVIII with acompound of formula XXIII

    r -- mg -- X . . . XXIII

in which R is lower alkyl and X is halogen.

We have found that compounds of formula I are anti-secretory agents,with a specific activity against gastric secretion and without anyanticholinergic activity. In particular the compounds reduce or inhibitthe secretion of gastric acid in animals; they are therefore useful forreducing or inhibiting gastric secretion (particularly the secretion ofgastric acid) and for the treatment of peptic ulceration. (The term"peptic ulceration" is used in its broad sense, as is conventional inthe art, to include both gastric ulceration and duodenal ulceration).

The dosage rates of compounds of formula I vary according to the valuesof R₁ ₋₄, but normally fall within the range 1/3-60 mg. of compound offormula I per kilogram of body weight of subject, preferablyadministered daily; in the cases of the more active compounds, dosagerates of 0.5-8 mg./kg. are acceptable. The anti-secretory activity ofthe compounds, which has been demonstrated in the stimulated, pylorusligated rat, has been found to be better in compounds of formula Iwherein X₁ and X₂ are oxygen than in similar compounds wherein X₁ and X₂are sulphur; substitution in rings A and B in general reduces activity.

The compounds of formula I may be administered orally, rectally orparenterally, preferably orally, the optimum dose rate varying with theactivity of the compounds. A preferred dosage rate for oraladministration is of the order of 25 mg. -4 g. daily, preferably 35mg. - 600 mg. daily, optionally in divided doses.

According to a further feature of the invention there are providedtherapeutic compositions which comprise a compound of formula I inassociation with pharmaceutical excipients known for the production ofcompositions suitable for oral, rectal or parenteral administration. Thecompositions preferably contain 0.1 - 90% by weight of a compound ofgeneral formula I.

Compositions for oral administration are the preferred compositions ofthe invention, and these are the known pharmaceutical forms for suchadministration, such as for example tablets, capsules, syrups andaqueous and oily suspensions.

The excipients used in the preparation of these compositions are theexcipients known in the pharmacist's art.

Preferred compositions are tablets wherein a compound of formula I ismixed with a conventional inert diluent such as lactose in the presenceof disintegrating agent, e.g. maize starch and lubricating agents e.g.magnesium stearate. Such tablets may, if desired, be provided withenteric coatings by known methods, for example by the use of celluloseacetate phthalate. Similarly capsules, for example hard or soft gelatincapsules, containing a compound of formula I, with or without otherexcipients, may be prepared by conventional means and, if desired,provided with enteric coatings in known manner. The tablets and capsulesmay conveniently each contain 25-500 mg. of a compound of formula I.Other, but less preferred, compositions for oral administration includefor example aqueous suspensions containing a compound of formula I inaqueous media in the presence of a non-toxic suspending agent e.g.sodium carboxymethylcellulose and dispersing agents, and oilysuspensions containing a compound of formula I in a vegetable oil forexample arachis oil.

Compositions of the invention suitable for rectal administration are theknown pharmaceutical forms for such administration, such as for examplesuppositories with cocoa butter or polyethylene glycol bases.

Compositions of the invention suitable for parenteral administration arethe known pharmaceutical forms for such administration, for examplesterile suspensions in aqueous and oily media or sterile solutions inpropylene glycol.

In the compositions of the invention the compounds of formula I may ifdesired be associated with other compatible pharmacologically activeingredients. For example antacids and acid adsorbents such as aluminiumhydroxide and magnesium trisilicate may be included in compositions fororal administration to give an immediate antacid effect. Otherpharmacologically active agents which may be associated with thecompounds of formula I include compounds active on the central nervoussystem, including short and long acting sedatives such as thebarbiturates and methaqualone, antihistaminic and/or antiemetic agentssuch as cyclizine and diphenhydramine, and anticholinergic agents suchas atropine.

Milk and milk solids are valuable in the treatment of peptic ulcer, andthe compositions of the invention include liquid and solid compositionsbased on milk and milk solids.

According to another aspect of the invention there is provided a methodof reducing gastric secretion, especially the secretion of gastric acid,which method comprises administering to a subject an anti-secretoryeffective amount of a compound of formula I preferably orally.

According to another aspect of the invention there is provided a methodof treating peptic ulcer which comprises administering to a subject ananti-secretory effective amount of a compound of formula I preferablyorally.

Typical compounds which exemplify the possible values of R₁ ₋₄ are thefollowing:

1,1-dimethyl-4-(9-xanthenyl)semicarbazide

1,1-pentamethylene-4-(9-xanthenyl)semicarbazide

2-methyl-1,1-pentamethylene-4-(9-xanthenyl)semicarbazide

1,1-tetramethylene-4-(9-xanthenyl)semicarbazide

1,1-hexamethylene-4-(9-xanthenyl)semicarbazide

1,1-diethyl-4-(9-xanthenyl)semicarbazide

1,1-dimethyl-4-(9-xanthenyl)thiosemicarbazide

4-hydroxy-4-(9-xanthenyl)semicarbazide

4-(1-chloro-9-xanthenyl)-1,1-dimethylsemicarbazide

1,1-dimethyl-4-(1-methyl-9-xanthenyl)semicarbazide

1,1,4-trimethyl-4-(9-xanthenyl)semicarbazide4-methyl-4-(9-xanthenyl)semicarbazide

4-methoxy-4-(9-xanthenyl)semicarbazide

4-isopropoxy-4-(9-xanthenyl)semicarbazide

4-isopropoxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide

4-(9-xanthenyl)semicarbazide

2-methyl-4-(9-xanthenyl)semicarbazide

4-(9-thiaxanthenyl)semicarbazide

4-hydroxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide

4-hydroxy-1,1-dimethyl-4-(9-thiaxanthenyl)semicarbazide

1-acetyl-4-(9-xanthenyl)semicarbazide

4-acetoxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide

1,1-dimethyl-4-propionyloxy-4-(9-xanthenyl)semicarbazide

4-isobutyryloxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide

4-butyryloxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide

4-hexanoyloxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide

1-ethoxycarbonyl-4-(9-xanthenyl)semicarbazide

1,2-dimethyl-4-(9-xanthenyl)semicarbazide

1-isopropyl-4-(9-xanthenyl)semicarbazide

1,1,2-trimethyl-4-(9-xanthenyl)semicarbazide

N-trimethylammonio-N'-9-xanthenylurea iodide

1,1-diethyl-4-hydroxy-4(9-xanthenyl)semicarbazide

4-hydroxy-1,1-dipropyl-4-(9-xanthenyl)semicarbazide

4-hydroxy-1,1-pentamethylene-4-(9xanthenyl)semicarbazide

4-hydroxy-1,1,2-trimethyl-4-(9-xanthenyl)semicarbazide

4-hydroxy-1,1-tetramethylene-4-(9-xanthenyl)semicarbazide

4-benzyloxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide

4-hydroxy-2-methyl-4-(9-xanthenyl)semicarbazide

4-hydroxy-1,2-dimethyl-4-(9-xanthenyl)semicarbazide

2-ethyl-4-hydroxy-4-(9-xanthenyl)semicarbazide

1,2-diethyl-4-hydroxy-4-(9-xanthenyl)semicarbazide

4-hydroxy-1,1-dimethyl-2-propyl-4-(9-xanthenyl)semicarbazide

4-hydroxy-1,2-dipropyl-4-(9-xanthenyl)semicarbazide

1,1-dibutyl-4-hydroxy-4-(9-xanthenyl)semicarbazide

4-hydroxy-1,1-(3-oxapentamethylene)-4-(9-xanthenyl)semicarbazide

1-acetyl-4-hydroxy-4-(9-xanthenyl)semicarbazide

2β-carboxyethyl-4-hydroxy-4 -(9-xanthenyl)semicarbazide lactam

4-hydroxy-2-methyl-1,1-pentamethylene-4-(9-xanthenyl)semicarbazide

4-ethyl-4-(9-xanthenyl)semicarbazide

1-ethyl-4-(9-xanthenyl)semicarbazide

1-ethyl-1-methyl-4-(9-xanthenyl)semicarbazide

4-(9-xanthenyl)thiosemicarbazide

4-methyl-4-(9-xanthenyl)thiosemicarbazide

4-hydroxy-4-(9-thiaxanthenyl)semicarbazide

4-acetoxy-1,1-dimethyl-4-(9-thiaxanthenyl)semicarbazide

1-ethyl-4-hydroxy-4-(9-xanthenyl)semicarbazide

4-acetoxy-1-acetyl-1-ethyl-4-(9-xanthenyl)semicarbazide

1,1-dimethyl-4-pivaloyloxy-4-(9-xanthenyl)semicarbazide

4-p-methoxyphenylacetoxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide

4-methoxyacetoxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide

4-ethoxalyloxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide

4-furoyloxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide

4-crotonifoxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide

4-benzoyloxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide

4-p-chlorobenzoyloxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide

4-ethoxycarbonyloxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide

1,1-dimethyl-4-phenylcarbamyloxy-4-(9-xanthenyl)semicarbazide

4-allyl-1,1-dimethyl-4-(9-xanthenyl)semicarbazide

4-cyclohexyl-1,1-dimethyl-4-(9-xanthenyl)semicarbazide

1,1-dimethyl-4-trimethylsilyloxy-4-(9-xanthenyl)semicarbazide

2-allyl-4-(9-xanthenyl)semicarbazide

2-allyl-4-methyl-4-(9-xanthenyl)semicarbazide

2-cyclohexyl-4-(9-xanthenyl)semicarbazide

2-cyclohexyl-4-methyl-4-(9-xanthenyl)semicarbazide

2-ethoxycarbonxyl-1,1-dimethyl-4-(9-xanthenyl)semicarbazide

2-ethoxycarbonyl-1,1,4-trimethyl-4-(9-xanthenyl)semicarbazide

1,1-diallyl-4-hydroxy-4-(9-xanthenyl)semicarbazide

1-cyclohexyl-1-methyl-4-hydroxy-4-(9-xanthenyl)semicarbazide

1-ethoxy-1-ethyl-4-hydroxy-4-(9-xanthenyl)semicarbazide

1-ethyl-1-methyl-4-hydroxy-4-(9-xanthenyl)semicarbazide

1,2-tetramethylene-4-(9-xanthenyl)semicarbazide

4-hydroxy-1,2-tetramethylene-4-(9-xanthenyl)semicarbazide

N'-hydroxy-N-trimethylammonio-N'-9-xanthenylurea iodide

N'-acetoxy-N-trimethylammonio-N'-9-xanthenylurea iodide4-(1-chloro-9-xanthenyl)-4-hydroxy-1,1-dimethylsemicarbazide

4-(1-fluoro-9-xanthenyl)-4-hydroxy-1,1-dimethylsemicarbazide

4-(2-fluoro-9-xanthenyl)-4-hydroxy-1,1-dimethylsemicarbazide

4-(1-chloro-9-xanthenyl)semicarbazide

4-(1-fluoro-9-xanthenyl)semicarbazide

4-(2-fluoro-9-xanthenyl)semicarbazide

4-hydroxy-1,1-dimethyl-4-(1-methyl-9-xanthenyl)semicarbazide

4-hydroxy-4-(1-methoxy-9-xanthenyl)-1,1-dimethylsemicarbazide

4-hydroxy-4-(1-hydroxy-9-xanthenyl)-1,1-dimethylsemicarbazide

4-(1-methyl-9-xanthenyl)semicarbazide

4-(1-methoxy-9-xanthenyl)semicarbazide

4-(1-hydroxy-9-xanthenyl)semicarbazide

4-β-methoxycarbonylpropionoxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide

1,1-dimethyl-4-methylthioacetoxy-4-(9-xanthenyl)semicarbazide

1,1-dimethyl-4-phenylacetoxy-4-(9-xanthenyl)semicarbazide

1,1-dimethyl-4-phenoxyacetoxy-4-(9-xanthenyl)semicarbazide

The above illustrates various values of A, B, X₁, X₂ and R₁ ₋₄ invarious combinations but of course it is to be understood that thesevalues are not limited to the combinations named; all possiblecombinations are within the invention and each value of A, B, X₁, X₂ andR₁ ₋₄ is to be considered as having been exemplified generically,independent of any particular combination of radicals.

The "acyl" moiety of the typical acyloxy compounds listed may of coursebe replaced by other acyl groups as hereinbefore defined. Examples ofacyl groups are the following:

Alkanoyl, e.g. acetyl, propionyl, butyryl, valeryl, octanoyl, stearyl,pivaloyl, ethoxalyl; substituted alkanoyl, e.g. phenylalkanoyl such asphenylacetyl; substituted phenylalkanoyl containing substituents such ashalogen, alkyl, alkoxy, hydroxy, amino, alkylamino, acylamino,dialklamino or nitro in the phenyl ring; phenoxyalkanoyl such asphenoxyacetyl; substituted phenoxyalkanoyl containing substituents suchas halogen, alkyl, alkoxy, hydroxy, amino, alkylamino, acylamino,dialkylamino, or nitro in the phenyl ring; haloalkanoyl such asbeta-chloropropionyl; alkoxyalkanoyl such as methoxyacetyl;alkylthioalkanoyl such as methylthioacetyl; dialkylaminoalkanoyl such asdiethylaminoacetyl; acyl alkanoyl such as acetoacetyl; cycloalkylalkanoyl such as cyclohexylacetyl; carboxyalkanoyl such asbeta-carboxypropionyl, carboxyalkenoyl such as beta-carboxyacryloyl, andsimilar groups in ester or salt form; heterocyclic alkanoyl such aspyridineacetyl;

alkenoyl e.g. crotonyl;

cycloalkanoyl e.g. cyclohexylcarbonyl;

aroyl e.g. benzoyl, naphthoyl, susbstituted benzoyl in which the phenylring contains substituents such as halogen, alkyl, alkoxy, hydroxy,amino, alkylamino, acylamino, dialkylamino, nitro or carboxyl (andesters and salts thereof);

residues of carbonic acid e.g. alkoxycarbonyl such as methoxycarbonyl,ethoxycarbonyl; substituted alkoxycarbonyl such as2-methoxyethoxycarbonyl, 2-phenoxyethoxycarbonyl,2-chloroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl;alkenyloxycarbonyl such as allyloxycarbonyl; cycloalkoxycarbonyl such ascyclohexyloxycarbonyl; aryloxycarbonyl such as phenoxycarbonyl andsimilar groups containing halogen, alkyl, alkoxy, hydroxy, amino,alkylamino, acylamino, dialkylamino or nitro substituents in the phenylring; aralkoxycarbonyl such as 2-phenylethoxycarbonyl;

N-substituted carbamoyl e.g. N-alkylcarbamoyl such as N-methylcarbamoyl;N,N-dialkylcarbamoyl such as N,N-dimethylcarbamoyl; N-phenylcarbamoyl;N,N-tetramethylenecarbamoyl; N,N-pentamethylenecarbamoyl;

N,n-3-oxapentamethylenecarbamoyl; N,N-3-thiapentamethylenecarbamoyl;

heterocyclic carbonyl e.g. groups comprising a carbon radical attachedto a 5 - 7 membered heterocycl ring containing up to two hetero atomsselected from oxygen, sulphur and nitrogen, such as thiotetrahydrothiophen, furan, tetrahydrofuran, pyridine, benzothiazole,benzofuran, xanthen, pyrimidine.

The following non-limitative examples illustrate the invention.

EXAMPLE 1

A solution of xanthydrol (4 g.) and 1,1-dimethy semicarbazide (2 g.) inethanolic acetic acid (1:1 50 ml.) was left overnight at roomtemperature. A dilution with ice/water, the solid obtained wasrecrystallised from chloroform/petroleum ether b.p. 60°C. to give1,1-dimethyl-4-(9-xanthenyl)semicarbazide m.p. 187°-188°C.

In a similar manner using the appropriate semicarbazide orthiosemicarbazide in place of 1,1-dimsemicarbazide, there were prepared:

1,1-pentamethylene-4-(9-xanthenyl)semicarbazide, m.p. 202°-202.5°C.(from chloroform/petroleum ether b.p. 40°-60°C.)

2-methyl-1,1-pentamethylene-4-(9-xanthenyl)semicarbazide, m.p.153°-155°C. (from petroleum ether b.p. 62-68°C., and a trace ofchloroform)

1,1-tetramethylene-4-(9-xanthenyl)semicarbazide, m.p. 203°-206°C. (fromchloroform/petroleum ether b.p. 40°-60°C.)

1,1-hexamethylene-4-(9-xanthenyl)semicarbazide, m.p. 201-202°C. (fromchloroform/petroleum ether b.p. 40°-60°C.)

1,1-diethyl-4-(9-xanthenyl)semicarbazide, m.p. 164°-168°C. (fromchloroform/petroleum ether b.p. 40°-60°C.)

1,1-dimethyl-4-(9-xanthenyl)thiosemicarbazide, m.p. 215°-217°C. (fromacetone)

4-hydroxy-4-(9-xanthenyl)semicarbazide, m.p. 184°-185°C. (from ethylacetate)

4-(1-chloro-9-xanthenyl)-1,1-dimethylsemicarbazide, m.p. 217°-219°C.(from acetone)

1,1-dimethyl-4-(1-methyl-9-xanthenyl)semicarbazide, m.p. 222°-223°C.(from acetone)

EXAMPLE 2

A solution of N-methyl-N-9-xanthenylcarbamoyl chloride (1.95 g.) intoluene (20 ml.) was added to an ice-cooled solution ofN,N-dimethylhydrazine (0.9 g.) in dry ether (10 ml.). After stirring for20 minutes at 0°C., the reaction mixture was washed with aqueous sodiumbicarbonate and water, dried and evaporated. Recrystallisation of theresidue from benzene gave 1,1,4-trimethyl-4-(9-xanthenyl)semicarbazide,m.p. 120°-123°C.

In a similar manner using the appropriate carbamoyl chloride andhydrazine hydrate, the following compounds were prepared:

4-methyl-4-(9-xanthenyl)semicarbazide, m.p. 146°-148°C. (fromchloroform/petroleum ether b.p. 62°-68°C.)

4-methoxy-4-(9-xanthenyl)semicarbazide, m.p. 141°-143°C. (fromchloroform/ether)

4-isopropoxy-4-(9-xanthenyl)semicarbazide, m.p. 134°C. (fromcyclohexane)

4-isopropoxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide, m.p. 157.5°C.

(from cyclohexane). (Prepared using N,N-dimethylhydrazine instead ofhydrazine hydrate)

N-Methyl-N-9-xanthenylcarbamoyl chloride was prepared by adding amixture of N-methyl-9-xanthenylamine (10 g.), triethylamine (7 ml.) anddry toluene (30 ml.) to a 10% solution of phosgene in toluene (250 ml.)at about -17°C. After overnight standing, the reaction product wasevaporated at less than 30°C. under reduced pressure to dryness. Theresidue was boiled with petroleum ether (b.p. 62°-68°C.), triethylaminehydrochloride filtered off, and the filtrate crystallised to giveN-methyl-N-9-xanthenylcarbamoyl chloride, m.p. 94°-95°C.

N-Methoxy-N-9-xanthenylcarbamoyl chloride was prepared by adding amixture of N-methoxy-N-9-xanthenylamine (7 g.), triethylamine (9 ml.)and toluene (10 ml.) to a 10% solution of phosgene in toluene (93 ml.)at -15°C. to -10°C. The reaction mixture was stirred at -10°C. for 15minutes and then allowed to attain room temperature over 1 hour.Evaporation in vacuo after filtering from triethylamine hydrochloridegave crude N-methoxy-N-9-xanthenylcarbamoyl chloride in the form of ayellow-brown oil. This was used dissolved in toluene.

N-Isopropoxy-N-9-xanthenylcarbamoyl chloride was prepared in a similarmanner in the form of a brown oil, and this was used dissolved intoluene.

EXAMPLE 3

a. A solution of S-phenyl N-hydroxy-N-9-xanthenylthiocarbamate (1.7 g.)in pyridine (12.5 ml.) containing triethylamine (0.4 ml.) was treatedwith hydrazine hydrate (0.78 ml.) at room temperature and left for 4hours. After heating on the steam bath for 1 hour and overnight standingat room temperature, the reaction mixture was diluted with water (35ml.) and filtered. The filtrate was diluted with a large volume ofwater; the resulting precipitate was crystallised fromdimethylformamide/toluene to give4-hydroxy-4-(9-xanthenyl)semicarbazide, m.p. 186°C.

In a similar manner using S-phenyl N-9-xanthenylthiocarbamate in placeof S-phenyl N-hydroxy-N-9-xanthenylthiocarbamate, there was prepared4-(9-xanthenyl)semicarbazide, m.p. 212°-214°C. (fromdimethylformamide/toluene).

In a similar manner using S-phenyl N-9-xanthenylthiocarbamate andmethylhydrazine, there was obtained2-methyl-4-(9-xanthenyl)semicarbazide, m.p. 183°-186°C. (from benzene).

The starting thiocarbamates were prepared as follows.S-Phenylthiocarbonyl chloride (2.8 ml.) was added to a stirred solutionof N-9-xanthenylhydroxylamine (2.13 g.) in pyridine (10 ml.) at 0°C.After overnight standing at 0°C., the reaction mixture was diluted withwater (100 ml.). The product was isolated in ether (washing with fresh5% aqueous sodium carbonate) and crystallised from acetone/petroleumether b.p. 62°-68°C. to give S-phenylN-hydroxy-N-9-xanthenylthiocarbamate, m.p. 177°-178°C.

In a similar manner using N-9-xanthenylamine in place ofN-9-xanthenylhydroxylamine, there was prepared S-phenylN-9-xanthenylthiocarbamate, m.p. 185°-187°C. (from acetone).

b. O-Chloroformyl ethyl methyl ketoxime (3.3 g.) was added dropwise to asolution of N-9-xanthenylhydroxylamine (4.26 g.) in dry pyridine (20ml.) at 0°C., and allowed to stand for 1 hour to give a crude solutionof ethyl methyl ketoxime N-hydroxy-N-9-xanthenylcarbamate. 5Ml. of thiswas treated with hydrazine hydrate (1.6 ml.) and left at roomtemperature for 4 days. The reaction mixture was then poured into alarge volume of water and the product isolated in ethyl acetate (35ml.); this solvent was evaporated and replaced by toluene (8 ml.) andevaporation continued to a residual volume of about 5 ml. The solidwhich separated was recrystallised from dimethylformamide/toluene togive 4-hydroxy-4-(9-xanthenyl)semicarbazide m.p. 184°C.

c. Ethyl N-9-xanthenylcarbamate (1 g.) and N,N-dimethylhydrazine (5 ml.)were added to a solution of sodium (0.1 g.) in methanol (10 ml.). Themixture was sealed in a pressure vessel and heated at 100°C. for 18hours, after which time it was evaporated to dryness. Recrystallisationfrom benzene and then carbon tetrachloride gave1,1-dimethyl-4-(9-xanthenyl)semicarbazide, m.p. 189°-191°C. (d)Hydrazine hydrate (0.82 ml.) was added to a solution of S-phenylN-9-thiaxanthenylthiocarbamate (679 mg.) in pyridine (7 ml.) containingtriethylamine (1.4 ml.) at 0°C. After 3 hours at 0°C., the reactionmixture was diluted with ice/water (50 ml.) and the resultingprecipitate recrystallised from chloroform/petroleum ether b.p.62°-68°C. to give 4-(9-thiaxanthenyl)semicarbazide, m.p. 199°-201°C.S-Phenyl N-9-thiaxanthenylthiocarbamate (m.p. 161°-165°C. exacetone/petroleum ether b.p. 62°-68°C.) was prepared fromS-phenylthiocarbamoyl chloride and 9-thiaxanthenylamine in a mannersimilar to that described in (a) for S-phenylN-hydroxy-N-9-xanthenylthiocarbamate.

EXAMPLE 4

S-Phenylthiocarbonyl chloride (6 ml.) in dioxan (20 ml.) was addeddropwise to a stirred, ice-cooled solution of N,N-dimethylhydrazine(5.04 g.) in dioxan (60 ml.). After stirring at 0°C. for 15 minutes, themixture (containing S-phenyl N',N'-dimethylthiocarbazate) was filteredinto a stirred solution of N-9-xanthenyl hydroxylamine (8.96 g.) inpyridine (136 ml.) containing triethylamine (6.4 ml.) at roomtemperature. After 24 hours, the reaction mixture was diluted withwater, and the resulting precipitate recrystallised fromdimethylformamide/toluene to give4-hydroxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide, m.p. 198°-200°C.

In a similar manner using N-9-thiaxanthenylhydroxylamine in place ofN-9-xanthenylhydroxylamine, there was prepared4-hydroxy-1,1-dimethyl-4-(9-thiaxanthenyl)semicarbazide, m.p. slowdecomposition from 181°C. (from dimethylformamide/toluene).

In a similar manner using O-isopropyl-N-9-xanthenylhydroxylamine (b.p.138°C./3 m.m., prepared by reacting O-isopropylhydroxylaminehydrochloride with xanthydrol in pyridine/ethanol in the presence ofacetic acid) in place of N-9-xanthenylhydroxylamine, there was prepared4-isopropoxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide, m.p. 159°C.(from cyclohexane).

EXAMPLE 5

4-(9-Xanthenyl)semicarbazide (0.59 g.) in pyridine (10 ml.) was treatedwith acetic anhydride (0.6 ml.) and left at room temperature for 24hours. Dilution with water (200 ml.) and crystallisation of theprecipitate obtained from dimethylformamide/toluene gaive1-acetyl4-)9-xanthenyl)semicarbazide, m.p. 226°-228°C.

EXAMPLE 6

A solution of 4-hydroxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide (897mg.) in pyridine (10 ml.) was treated with acetic anhydride (612 mg.)and left at room temperature for 24 hours. Dilution with ice/water (100ml.) and crystallisation of the resulting precipitate fromacetone/petroleum ether b.p. 62°-68°C. gave4-acetoxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide, m.p. 120° -121°C.

In a similar manner using propionic anhydride in place of aceticanhydride there was obtained1,1-dimethyl-4-propionyloxy-4-(9-xanthenyl)semicarbazide, m.p.123°-124°C. (from acetone/petroleum ether b.p. 40°-60°C.).

In a similar manner using isobutyric anhydride there was obtained4-isobutyryloxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide, m.p.131°-132°C. (from acetone).

In a similar manner using butyric anhydride there was obtained4-butyryloxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide, m.p. 115°-117°C.(from acetone/petroleum ether b.p. 62°-68°C.).

In a similar manner using hexanoic anhydride there was obtained4-hexanoyloxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide.

EXAMPLE 7

A solution of 4-acetoxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide (143mg.) in methanol (5 ml.) was treated with 1N sodium hydroxide solution(0.63 ml.) and left at room temperature for 2 hours. Acetic acid (0.05ml.) was then added and the reaction mixture diluted with water (5 ml.).The resulting precipitate was dried to give4-hydroxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide, m.p. 196°-198°C.

In a similar manner, crude4-acetoxy-1-acetyl-4-(9-xanthenyl)semicarbazide (prepared by the methodof Example 6 from 4-hydroxy-4-(9-xanthenyl)semicarbazide) was hydrolysedto give 1-acetyl-4-hydroxy-4-(9-xanthenyl)semicarbazide, m.p.173°-176°C. (from dimethylformamide/toluene).

EXAMPLE 8

Xanthen-9-carbonyl azide (4 g.) in benzene (50 ml.) was warmed to50°-60°C. until nitrogen evolution ceased. To the filtered solution(containing 9-xanthenyl isocyanate) there was addedethoxycarbonylhydrazine (1.67 g.) in benzene (10 ml.). After 1 hour, thereaction product was filtered and the residue recrystallised fromdimethylformamide/toluene to give1-ethoxycarbonyl-4-(9-xanthenyl)semicarbazide, m.p. 188°-191°C.

In a similar manner, using methylhydrazine and N,N'-dimethylhydrazine inplace of ethoxycarbonylhydrazine, there were obtained respectively2-methyl-4-(9-xanthenyl)semicarbazide, m.p. 188°-190°C. (from methanol)and 1,2-dimethyl-4-(9-xanthenyl)semicarbazide, m.p. 118°-119°C.

Xanthen-9-carbonyl azide used above was prepared as follows.Xanthen-9-carbonyl chloride [6.65 g., m.p. 87°-90°C., prepared byrefluxing xanthen-9-carboxylic acid (6.34 g.) with thionyl chloride (25ml.) for 2 hours and evaporating to dryness] was dissolved in acetone(25 ml.) and stirred in an ice bath. Sodium azide (2.5 g.) in water (10ml.) was added slowly at 12°-17°C., and then water (10ml.) was added tothe mixture at 10°C. The precipitate thus obtained was filtered off,washed with cold 50% aqueous acetone (20 ml.) and dried. It was thenrecrystallised from ether at -80°C. to give xanthen-9-carbonyl azide,decomposition point 72°C.

EXAMPLE 9

Xanthen-9-carbonyl azide (1 g.) and N,N-dimethylhydrazine (0.4 ml.) indry benzene (15 ml.) were warmed to 60°C., causing an effervescencewhich was complete in 30 minutes. After 1 hour at 25°C., the precipitatewas collected to give 1,1-dimethyl-4-(9-xanthenyl)semicarbazide, m.p.189°-195°C.

EXAMPLE 10

Acetone 4-(9-xanthenyl)semicarbazone (274 mg.) in methanol (38 ml.),acetic acid (1 ml.) and water (1 ml.) was treated with hydrogen in thepresence of platinum oxide (25 mg.). When reduction was complete, thereaction mixture was filtered, the filtrate evaporated to dryness, andthe residue recrystallised from benzene to give1-isopropyl-4-(9-xanthenyl)semicarbazide, m.p. 161.5°-162.5°C.

EXAMPLE 11

4-Benzyloxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide (389 mg.) inethanol (25 ml.) was treated with hydrogen in the presence of 10%palladium charcoal (80 mg.). When hydrogenation was complete, thereaction mixture was filtered, the product washed from the catalyst withdimethylformamide (10 ml.) and the solution evaporated to dryness invacuo. The residue was recrystallised from dimethylformamide/toluene togive 4-hydroxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide, m.p.192°-193°C.

In a similar manner from the appropriate4-benzyloxy-4-(9-xanthenyl)semicarbazide, there were prepared:

1,1-diethyl-4-hydroxy-4-(9-xanthenyl)semicarbazide, (fromdimethylformamide) m.p. 208°C.

4-hydroxy-1,1-dipropyl-4-(9-xanthenyl)semicarbazide

4-hydroxy-1,1-pentamethylene-4-(9-xanthenyl)semicarbazide, m.p. 192°C.

(from dimethylformamide/toluene/petroleum ether b.p. 60°-80°C. 1:1:1).

4-hydroxy-4-(9-xanthenyl)semicarbazide

4-hydroxy-1,1,2-trimethyl-4-(9-xanthenyl(semicarbazide

4-hydroxy-1,1-tetramethylene-4-(9-xanthenyl)semicarbazide

The starting materials were prepared as follows. A mixture ofO-benzyl-N-9-xanthenylhydroxylamine (3.03 g.) and triethylamine (1 ml.)in dry toluene (30 ml.) was added dropwise to a 10% solution of phosgenein toluene (30 ml.) maintained at -20°C. After 15 minutes at thistemperature and 1 hour to rise to room temperature, the reaction mixturewas filtered and the filtrate evaporated in vacuo to give crudeN-benzyloxy-N-9-xanthenylcarbamoyl chloride in the form of a brown oil.A solution of this material (about 1 equivalent) in toluene (30 ml.) wasadded to 1,1-dimethylhydrazine (0.6 g.), triethylamine (1g.) and toluene(30 ml.) at room temperature. After overnight stirring, the reactionmixture was filtered and the filtrate evaporated to dryness in vacuo.Recrystallisation of the residue from cyclohexane/petroleum ether b.p.62°-68`C. gave 4-benzyloxy1,1-dimethyl-4-(9-xanthenyl)semicarbazide,m.p. 117°C.

In a similar manner there were prepared:

4-benzyloxy-1,1-diethyl-4-(9-xanthenyl)semicarbazide, (from cyclohexane)m.p. 126.5°-127.5°C.4-benzyloxy-1,1-dipropyl-4-(9-xanthenyl)semicarbazide, m.p. 82°C. (fromchloroform/petroleum ether b.p. 62°-68°C.)

4-benzyloxy-1,1-pentamethylene-4-(9-xanthenyl)semicarbazide m.p.143°-144°C. (from chloroform/petroleum ether b.p. 62°-68°C.)

4-benzyloxy-4-(9-xanthenyl)semicarbazide

4-benzyloxy-1,1,2-trimethyl-4-(9-xanthenyl)semicarbazide

4-benzyloxy-1,1-tetramethylene-4-(9-xanthenyl)semicarbazide

EXAMPLE 12

A solution of 1,1-dimethylsemicarbazide (1.03 g.) in dry dioxan (20 ml.)was stirred at room temperature for 3 hours with sodium hydride (0.48g., 50% oil dispersion). 9-Chloroxanthen (2.16 g.) in dioxan (15 ml.)was added dropwise and, after overnight stirring, the mixture was pouredinto ice/water (100 ml.) containing saturated aqueous sodium bicarbonate(5 ml.). The resulting precipitate was boiled with benzene (20 ml.),cooled and the separated solid extracted with hot carbon tetrachloride(15 ml.). On cooling there was obtained1,1-dimethyl-4-(9-xanthenyl)semicarbazide, m.p. 193°-194°C.

EXAMPLE 13

Sodium hydride (0.48 g., 50% oil dispersion) was added to a solution of1,1-dimethyl-4-(9-xanthenyl)semicarbazide (2.83 g.) in tetrahydrofuran(40 ml.). After 2 hours under reflux, methyl iodide (1.32 ml.) was addedand refluxing continued for 5 hours. Methanol (5 ml.) was then added tothe cooled and filtered reaction mixture, and the solution evaporated to10 ml. Chloroform (25 ml.) was added, the solution filtered and thenevaporated. The portion of the residue insoluble in hot petroleum etherb.p. 40°-60°C. (2 × 15 ml.) was recrystallised from chloroform to give1,1,2-trimethyl-4-(9-xanthenyl)semicarbazide, m.p. 141°-142°C.

EXAMPLE 14

A suspension of N-methyl-N-nitroso-N'-xanthenylurea (520 mg.) andplatinum oxide (110 mg.) in methaol (20 ml.) was shaken under hydrogenfor 12 hours. After filtration, the reaction mixture was evaporated invacuo to about 1.5 ml. and diluted with water. The precipitate wascollected and the benzene-soluble portion crystallised from benzene andfrom benzene/petroleum ether b.p. 62°-68°C. to give2-methyl-4-(9-xanthenyl)semicarbazide, m.p. 173°-176°C.

The starting material was prepared as follows. A suspension ofN'-methyl-N-9-xanthenylurea (5.08 g.) in acetic acid (75 ml.) and water(5 ml.) at 5°C. was treated with a solution of sodium nitrite (1.52 g.)in water (5 ml.). After ice cooling, the precipitate was collected andrecrystallised from ethanol and from benzene/petroleum ether b.p.62°-68°C. to give the required product, m.p. 151°C.

EXAMPLE 15

A mixture of 1,1-dimethyl-4-(9-xanthenyl)semicarbazide (259 mg.), methyliodide (0.1 ml.) and acetone (10 ml.) was refluxed for 7 hours. Aftercooling, the precipitate was recrystallised from nitromethane to giveN-trimethylammonio-N'-9-xanthenylurea iodide, m.p. 196°C.

EXAMPLE 15A

A solution of 1,1-dimethyl-4-(9-xanthenylidene)semicarbazide (100 mg.)in dimethylformamide (7 ml.) was treated with 10% palladium/charcoal andshaken in an atmosphere of hydrogen. After 1 hour, platinum oxide (20mg.) was added and shaking continued a further hour. The mixture wasfiltered and the filtrate evaporated to dryness in vacuo. The residuewas extracted with boiling carbon tetrachloride, filtered, and thefiltrate evaporated to a small bulk; cooling gave1,1-dimethyl4-(9-xanthenyl)semicarbazide, m.p. 190°-193°C.

The starting material was prepared as follows.S-Phenylthiocarbonylchloride (6 ml.) in dioxan (20 ml.) was addeddropwise to a stirred, ice-cooled solution of N,N-dimethylhydrazine(5.06 g.) in dioxan (60 ml.). After stirring at 0°C. for 15 minutes, themixture (containing S-phenyl N',N'-dimethylthiocarbazate) was filteredinto a stirred solution of xanthone imine (4.1 g.) in pyridine (70 ml.)and triethylamine (3 ml.) at room temperature. After 11 days, themixture was diluted with ice-water (150 ml.) and filtered. After furtherdilution (500 ml.) the mixture was extracted with ether. Evaporation ofthe ether solution gave a yellow gummy solid. Trituration of this with alittle ether gave 1,1-dimethyl-4-(9-xanthenylidene)semicarbazide, m.p.168°-169°C. (from acetone/petroleum ether, b.p. 40°-60°C.).

[satisfactory elemental analyses were obtained for the compoundsprepared in the above Examples. Structures were confirmed by infra redspectroscopy and, where necessary, by nuclear magnetic resonancespectroscopy. In many cases, the compounds melted with decomposition atthe temperatures described.]

EXAMPLE 16

In the preparation of tablets, mixtures of the following type may betabletted in conventional manner:

    Compound of formula I                                                                          10 - 90%                                                     Lactose           0 - 80%                                                     Maize starch      5 - 10%                                                     Magnesium stearate                                                                             ca. 1%                                                       Microcrystalline cellulose                                                                      0 - 90%                                                                      (by weight)                                              

EXAMPLE 17

In the preparation of tablets the following mixture was dry granulatedand compressed in a tabletting machine to give tablets containing 50 mg.of active ingredient:

    4-hydroxy-1,1-dimethyl-4-                                                                      25%                                                          (9-xanthenyl)semicarbazide                                                    Maize starch     10%                                                          Lactose          20%                                                          Magnesium stearate                                                                              1%                                                          Microcrystalline cellulose                                                                     to 100% by                                                                    weight                                                   

EXAMPLE 18

In the preparation of enteric coated tablets, tablets prepared asdescribed in Example 17 were coated with sanderac varnish and thencoated with cellulose acetate phthalate using a solution of 20%cellulose acetate phthalate and 3% diethyl phthalate in a mixture ofequal parts of industrial alcohol and acetone.

EXAMPLE 19

In the preparation of tablets the following mixture was dry granulatedand compressed in a tabletting machine to give tablets containing 5 mg.of active ingredient:-4-hydroxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide (10 g.), lactose (10g.), and maize starch (5 g.).

EXAMPLE 20

In the preparation of enteric coated tablets, the tablets described inExample 19 were given a thin coat of shellac followed by 20 coats ofcellulose acetate phthalate.

EXAMPLE 21

In the preparation of capsules, a mixture of the ingredients describedin Example 19 was encapsulated in hard gelatin capsules. Enteric coatingwas applied by conventional dipping in cellulose acetate phthalate.

EXAMPLE 22

The following mixture was compressed into tablets in a conventionalmanner:

    4-hydroxy-1,1-dimethyl-4-                                                                      25%                                                          (9-xanthenyl)semicarbazide                                                    Sodium bicarbonate                                                                             75%                                                          Peppermint oil   q.s.                                                     

EXAMPLE 23

In the preparation of capsules a mixture of equal parts by weight of4-hydroxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide and lactose wasencapsulated in hard gelatin capsules, each capsule containing 50 mg. ofthe semicarbazide.

EXAMPLE 24

In the preparation of enteric coated capsules, the capsules of Example23 were coated with cellulose acetate phthalate in the conventionalmanner.

EXAMPLE 25

Suppositories weighing 1g. and containing 50 mg.4-hydroxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide were prepared inconventional manner using a base consisting of

    Polyethylene glycol 4000                                                                       33%                                                          Polyethylene glycol 6000                                                                       47%                                                          Water            20%                                                      

EXAMPLE 26

A solution for parenteral administration was prepared comprising4-hydroxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide in propylene glycol,100 mg./2 ml. sterilised by filtration.

Compositions similar to those described in Examples 16 - 26 were alsoprepared, containing other compounds of formula I previously describedin place of 4-hydroxy-1,1-dimethyl-4-(9-xanthenyl)semicarbazide.

We claim:
 1. Compounds of formula I ##EQU17## wherein Xn represents thegroup ##SPC3##in which the rings A and B may optionally contain 1additional substituent selected from halogen, lower-alkyl, lower-alkoxyand hydroxy, said substituent when present being in either the 1 or 2position of the ring; R₁ is hydrogen, lower-alkyl or lower-alkenyl; R₂is hydrogen or lower-alkyl; R₃ is hydrogen or lower-alkyl; R₄ ishydrogen or lower-alkyl; together with pharmaceutically acceptable acidaddition salts of compounds of formula I; and, when R₃ and R₄ are eachlower-alkyl, pharmaceutically acceptable quaternary salts of compoundsof formula I
 2. Compounds of formula IA ##SPC4##in which R₁ is hydrogen,lower alkyl or lower alkenyl; R₂ is hydrogen or lower alkyl; R₃ ishydrogen or lower alkyl; R₄ is hydrogen or lower alkyl; together withpharmaceutically acceptable acid addition salts of compounds of formulaIA.
 3. Compounds as claimed in claim 2 in which R₁ and R₂ are hydrogen,R₃ is hydrogen or lower alkyl and R₄ is hydrogen or lower alkyl.
 4. Thecompound of claim 2 which is 4-(9-xanthenyl)semicarbazide.
 5. Thecompound of claim 2 which is 1,1-dimethyl-4-(9-xanthenyl)semicarbazide.